Neuroendocrine lung cancer is among the most common cancers of mankind and demonstrates a strong association with cigarette smoking. We have developed the first and only in vivo model of neuroendocrine ling cancer by imposing hamsters simultaneously to hyperoxia and tobacco-related nitrosamines. This novel system allows to study the mechanisms of initiation and progression of this deadly disease and to develop strategies for its prevention and therapy. During the past three years of NIH-funded research, we have characterized the pathology, pathogenesis, and neuroendocrinology of the hamster neuroendocrine lung tumors in detail, and we have developed continuous cell lines from two such tumors. We have provided convincing evidence that during the stage of tumor initiation, stimulation of nicotinic cholinergic receptors play a crucial role in the molecular mechanisms which cause continuous cell proliferation. Moreover, we have shown that overexpression of ras-family oncogenes is found in the tumors and cell lines. Using the hamster model and these tumor cell lines, we will study in detail the molecular role f nicotinic cholinergic receptors at the stage of tumor initiation and the modulation of this receptor during progression. Moreover, we will screen the hamster tumors and cell lines derived from them for the expression and mutation of oncogenes pertinent to human and rodent lung cancers. Subsequently, we will determine at what stag of tumor development these changes in gene expression occur and how this relates to the already documented stages of pathogenesis and modulations in neuroendocrine markers. During the third year of this continuation project, we will then begin to explore the association between alterations in gene expression and functional modulations of the nicotinic cholinergic receptor . Our data are highly relevant to human neuroendocrine lung cancer and will provide a meaningful basis for the prevention and therapy of this common lung cancer type.